Efgartigimod as a first line attack therapy in demyelinating diseases of the central nervous system

Treatment tested

• Efgartigimod alfa

  IgG receptor FcRn large subunit p51 antagonist

Placebo or sham

• placebo

Other measures (12)

Inclusion: - 1. Subjects aged ≥18 years of any gender (male, female, inter/divers) are eligible, biological sex assigned at birth will be documented at screening - 2. Presence of a clinical attack† consistent with one of the following diagnoses according to established criteria: CIS§ (1), RRMS (2), AQP4+ NMOSD (3), MOGAD (4) - 3. Provision of signed and dated written informed consent by the subject or an impartial witness, and the ability to comply with protocol requirements - 4. Subjects are eligible if the first Investigational Medicinal Product (IMP) infusion can be initiated within 10 days of attack onset and no later than the 5th IVMP administration - 5. Pre-attack EDSS (Expanded Disability Status Scale) ¶, including target neurological deficits (TND)‡ functional system scores (FSS), and corrected HCVA (High Contrast Visual Acuity) in case of ON (Optic Neuritis; habitual or best-corrected) must be either documented or retrospectively assessable - 6. Pre-attack EDSS¶ ≤6.0 - 7. EDSS during current attack 3.0 - 7.5 - 8. At least moderate attack severity, defined as the presence of at least one of the following TND‡ at screening: · for pyramidal, brainstem, cerebellar subscales ΔFSS⁑ >2.0 and minimal FSS ≥3.0 · for sensory subscales ΔFSS⁑>2.0 and minimal FSS ≥4.0 · in ON HCVA ≤20/200 (≥1.0 logMAR); if documented previous visual deficits Δ⁑ ≥2 lines ETDRS (Early Treatment Diabetic Retinopathy Study; 0.2 logMAR); ⁑ Δ is defined as the change from the pre-attack baseline (most recent assessment prior to the current attack during remission) to the score assessed at screening Exclusion: - 1. Current attack presenting with predominant involvement of the cerebral FSS at screening - 10. Known hypersensitivity to efgartigimod, methylprednisolone, prednisone and any contained excipients of the IMPs - 11. Clinically significant disease, recent major surgery within 3 months prior to screening, or planned major surgery during the study period - 12. Any other medical condition that, in the investigator’s opinion, would confound the accurate assessment of clinical symptoms or put the participant at undue risk - 13. Participation in another clinical trial involving investigational drugs or medical devices at the time of enrollment, or participation in such a trial within 30 days prior to enrollment (or within five half-lives of the investigational product, whichever is longer), if this may interfere with the endpoints of the present study - 2. Use of the following previous or concomitant therapies a. anti-FcRn therapy ≤3 months before screening b. IVMP*; plasma exchange or immunoadsorption; intravenous, intramuscular or subcutaneous IgG received ≤4 weeks before screening c. any form of CAR T-cell therapy or hematopoietic stem cell transplantation (HSCT) before screening; * except for the administration of ≤5 IVMP for the current attack - 3. For patients without best-corrected HCVA data within 12 months before onset of the current attack any visually significant ocular pathology (e.g., retinal diseases, cataracts, glaucoma, etc.) in the affected eye constitutes an exclusion criterion; congenital color-blindness is not disqualifying - 4. Clinically active or chronic uncontrolled infection (bacterial, fungal or viral), including patients who test positive for an active viral infection at screening with: a. Human Immunodeficiency Virus (HIV) positive serology associated with an Acquired Immune Deficiency Syndrome (AIDS)-defining condition or with CD4 ≤200 cells/mm3 b. Hepatitis B Virus (HBV): serologic panel test results indicative of an active (acute or chronic) infection c. Hepatitis C Virus (HCV): serology positive for anti-HCV antibodies - 5. Known common variable immunodeficiency - 6. History of malignancy unless considered cured by adequate treatment with no evidence of recurrence for ≥3 years before screening. Adequately treated participants with the following cancers may be included at any time: a. Basal cell or squamous cell skin cancer b. Carcinoma in situ of the cervix c. Carcinoma in situ of the breast d. Incidental histological finding of prostate cancer (TNM stage T1a or T1b) - 7. Live or live-attenuated vaccine received <4 weeks before screening. Receiving an inactivated, sub-unit, polysaccharide, or conjugate vaccine any time before screening is not exclusionary, however, these vaccines must not be administered within 48 hours before IMP infusion - 8. Pregnant or lactating state or intention to become pregnant during the study - 9. Severe renal impairment with eGFR <30 mL/min/1.73 m2 at screening

To assess the efficacy of efgartigimod compared with placebo as add-on to standard intravenous methylprednisolone (IVMP) therapy in patients with moderate-to-severe attacks† of CIS/RRMS, AQP4+ NMOSD or MOGAD